An estrogen-sensitive hypothalamus-midbrain neural circuit controls thermogenesis and physical activity.

Estrogen receptor–α (ERα) expressed by neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (ERα vlVMH ) regulates body weight in females, but the downstream neural circuits mediating this biology remain largely unknown. Here we identified a neural circuit mediating the metabolic effects of ERα vlVMH neurons. We found that selective activation of ERα vlVMH neurons stimulated brown adipose tissue (BAT) thermogenesis, physical activity, and core temperature and that ERα vlVMH neurons provide monosynaptic glutamatergic inputs to 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus (DRN). Notably, the ERα vlVMH → DRN circuit responds to changes in ambient temperature and nutritional states. We further showed that 5-HT DRN neurons mediate the stimulatory effects of ERα vlVMH neurons on BAT thermogenesis and physical activity and that ERα expressed by DRN-projecting ERα vlVMH neurons is required for the maintenance of energy balance. Together, these findings support a model that ERα vlVMH neurons activate BAT thermogenesis and physical activity through stimulating 5-HT DRN neurons.